From Girolamo Fracastoro to Joseph Lister : Pioneers of antiseptic procedures in medical and sanitary practices… and beyond !

Antiseptics are antimicrobial substances that can be applied on living tissue /skin/ cell membrane /plant cell wall/ … of people, animals, plants, … – without harming the host – to reduce the chance of microbial infection, sepsis or putrefaction to occur. In practice, antiseptics are used to kill or eliminate microorganisms and/or inactivate viruses on living tissues (intact or damaged skin, mucous membranes, plant cell walls, etc.). Some antiseptics are true germicides, killing microbial cells, while others are “microbiostatic” and only prevent or inhibit microbial growth. These substances are to be discerned from disinfectants, that are mainly used to destroy microbes found on non-living objects or any material (named fomes or fomites) carrying infectious organisms, as well as from antibiotics that act much more specific on selected pathogenic bacteria or fungi – not on viruses -, that can be applied topically or transported through the lymphatic system and that are used in medical practice to heal (mainly already) infected patients.

The miasma theory of disease versus the germ theory of disease

The Greek general and historian Thucydides (c.460-c.400 BC ), who described in his “History of the Peleponnesian War” the plague of Athens, is considered the first to have stated that disease could be spread from person to person and also by “seeds” present in air (Nutton, 1983). The Roman poet Lucretius ( 99-55 BC) wrote in his poem “ De Rerum Natura“ (On the Nature of Things ) that the world contained various “seeds” that could sicken a person if taken in as air or as food. Equally Roman scholar and writer Marcus Terentius Varro (116-27 BC) wrote in his “Rerum Rusticarum Libri III“ (Three Books on Agriculture) that swamps are to be avoided since certain minute creatures that cannot be seen by the eyes float in the air and can enter the body and cause disease.

Thucidides (c.460 – c.400 BC) Varro (116–27 BC)

The influential Greek physician Galen (or Galenus) (129-c.200 AC) speculated further that some patients carry “seeds of fever”. He also spread the (wrong) opinion that wound-pus was important for healing of wounds and that plagues were caused and spread by “seeds of plague ” present in “bad air”. This is known as Galen’s “miasma theory” of disease transmission that remained dominant among scientists and physicians for the next 16 centuries till the germ theory of disease was experimentally proven by Robert Koch in 1876. This “miasma theory” held that infectious diseases were caused by a noxious form of “bad or polluted air”, emanating from rotting organic matter, contaminated water and poor hygienic conditions; it was finally killed by the conclusive experiments of L. Pasteur and R. Koch (Vandamme, 2019).

3. Early history of use of antiseptics and disinfectants to treat infections caused by “spores of disease.

Already in the 13th century – and contradicting Galen – some medieval surgeons advocated wounds to be cleaned from pus and the use of wine-soaked bandages as an antiseptic treatment. Famous was the Italian Dominican friar Theodoric Borgognoni (1205-1296), who practiced medicine and surgery next to his religious duties as Bishop of Cervia and combining these functions as the private physician of Pope Innocent IV. With his French pupil, physician Henri de Mondeville (1260-1320), he also promoted the use of anaesthetics such as a sponge soaked in dissolved solutions of opium, hemlock, mulberry juice, ivy, etc., held under the nose of patients. His major medical four-volume treatise “Cyrurgia” covered all aspects of surgery at that time and broke with many traditional practices handed over via the ancient Greek and Arabic surgeons. However his theories and practices were bitterly opposed for several centuries to come (Edwards, 1976) !

From the 16th century onwards these ancient “miasma” beliefs were put to the test! The first scholar to suggest that disease might be infectious and can be treated is the Italian physician, poet, mathematician, geographer and astronomer Girolamo Fracastero (1478-1553). Born in Verona, then in the Republic of Venice, and educated at Padua, he was appointed already at age 19 at the University of Padua, where he adhered to the philosophy of atomism and rejected “hidden causes/powers” as scientific base. He lived and practiced as a physician in Verona. Fracastero used as a first the Latin term “fomes” (in English “fomites “), meaning “tinder” in the sense of ignition-/ infectious-agent, in his assay on contagion “De Contagione et Contagiosis Morbis”, published in 1546 : “I call fomes such things as clothes, linen, wooden objects , and things of that sort , which though not themselves corrupted, can nevertheless preserve the original germs of the contagion and infect by means of these“. He also proposed that epidemic diseases are caused by transferable tiny particles or “spores of disease” that could transmit infection by direct or indirect contact or even without contact over long distances and he gave a first description of typhus disease. Also the name “ syphilis” is derived from Fracastero’s 1530 epic poem “ Syphilidis sive Morbi Gallici” (Syphilis or the French Disease ), about a shepherd boy named Syphilus who insulted the Greek god Apollo, and was punished by Apollo with this horrible disease. In this text a cure was suggested, based on mercury and “guaiaco”, a tropical wood resin, indicating an “antiseptic“ activity. A portrait of Fracastoro, now in the National Gallery in London, UK, has been attributed to the renown Italian painter Titian (c. 1528). Speculation goes that Titian had painted his portrait in exchange for syphilis treatment. A bronze statue was erected in his honor by the citizens of Padua and his native town Verona commemorated its famous son with a marble statue in 1559. A lunar crater “Fracastorius “ has been named after him! His “spores of disease”-theory lingered on for over 3 centuries before being superseded by the germ theory. The origin of the “spores of disease“ was then unknown and belief in spontaneous generation was common, even by scholars up till the 18th century (Vandamme, 2019). Gradually these “spores of disease“ became tangible and visible !

In the 1650’s, the German Jesuit, scholar and polymath Athanasius Kircher (1602-1680 ), spending most of his lifetime in Rome, was struck by the many victims of the 1656 bubonic plague epidemy. As early as 1646, he had studied diseases by investigating the blood of plague victims, using a simple microscope. In his book “Scrutinium Pestis Physico Medicum” of 1658, he wrote about the presence of “little worms” or “animalcules” in the blood and concluded that the plague disease was caused by those small organisms. What he observed then were most probably red or whiteblood cells rather than the bacterial plague agent, Yersinia pestis. He also proposed antiseptic measures to prevent the spread of disease, such as quarantine, burning clothes of the infected and wearing facemasks to prevent the inhalation of such “little worms”.

The then nascent “germ theory of disease” was endorsed by the French physician and writer Nicolas Andry de Bois-Regard (1658-1742). His medical work led to his book “ De la génération des vers dans les corps de l’homme”, published in 1700, and translated into English in 1701 as “An Account of the Breeding of Worms in Human Bodies”. The book described his experiments with the microscope, based on the earlier work of Antoni van Leeuwenhoek (1632-1723). Unlike van Leeuwenhoek, his purpose was specifically medically oriented, and his experiments led him to believe that the microorganisms he called “worms” were responsible for smallpox and other diseases.

During the years 1714 to 1721, Richard Bradley (1688-1732), later to become the first Professor of Botany at Cambridge University, UK, proposed a unified “ living agent theory” for the cause of infectious diseases of plants and animals and of the human plague (infections that he called “all pestilential distempers “). His theory was based on his experimental studies of plants and their diseases and from microscopic observation of “animalcules” in different naturally occurring and artificial environments. He concluded that there was a microscopic world of “poisonous insects”, that lived and reproduced under the appropriate conditions, and that infectious diseases of plants, animals and humans were caused by such small “insects”. However this “living agent cause” of infectious diseases was not accepted by his scientific colleagues (Santer, 2009 ).

Richard Bradley (1688-1732)

As a famous medical practitioner, the Austrian Marcus Antonius von Plenčič (1705-1786) made careful observations of infectious (or contagious) human diseases. In applying a rigorous logic, he developed a remarkable theory of the nature of “contagion”, stating that specific “living animalcules “ were responsible for specific diseases. He was one of the first to recognize the etiological significance of van Leeuwenhoek’s animalcules. Plenčič’s theory is set out in his book “Opera medico-physica” of 1762. He believed that contagious diseases were caused by microorganisms, which he called “animalcula minima,” or “animalcula insensibilia.” He stated ”these microorganisms are both specific and constant: a given animalcule always causes the same disease, and attacks a specific host ; they are carried over by the air, as the means of infection (that he named “materia animata,” “miasma animatum,” “miasma verminosum,” “seminia animata,” and “principium aliquod seminale verminosum” ) “, emphasizing his conviction of the animal nature of the microorganisms involved. Their speed of reproduction accounted for why a minute amount of an inoculum (as of smallpox) can cause disease. He also noted the incubation period in infectious diseases and discussed the possibility that microorganisms might have periods of latency, after which, conditions having become more suitable, they might resume their pathogenic activity. He was aware of disposition towards a specific disease, immunity (including that resulting from a previous attack), mixed infection, antibiosis, and chemotherapy. In recommending his theory, Plenčič suggested the use of remedies acting directly upon the microorganisms, among them antihelmintics and antiseptics (mostly toxic compounds based on heavy metals). His etiological theory allowed all the contagious diseases of man (including smallpox, plague, and scarlet fever), animals (including cattle plague), and even plants (for example, wheat rust) to be considered on a common basis (Rosen, 1958; Peller, 1963 ; Porter, 1999). Again this “living agent cause” theory – whether named animalcules, little worms, poisonous insects,… – of infectious diseases was not accepted by his contemporary scientists of the 18th century (Santer, 2009 ).

Marcus Antonius von Plenčič (1705-1786)

4. Undervalued pioneers of antiseptic procedures in the 19th century

An early pioneer of real antiseptic procedures was the Hungarian physician Ignaz Philipp Semmelweis (1818-1865). He found that the incidence of child bed fever (puerperal fever), common and often fatal in mid-19th century hospitals, could be drastically lowered by introducing hand disinfection in obstetrical clinics. While working at the Vienna General Hospital, he had noticed that the doctors’ ward had three times the mortality of the midwives’ wards; Semmelweis made the connection between high puerperal fever cases following examination of delivering women and births assisted by doctors and medical students as compared to the low number of cases, when assisted by midwives. Assuming that puerperal fever was a contagious disease caused by some unknown “cadaverous material“ , he proposed in 1847 that doctors wash their hands with chlorinated lime water (calcium hypochlorate) after autopsy work and before examining pregnant women; this resulted in a sudden reduction in mortality rate from 18 % to 2.2 % within one year (Hanninen et al., 1983). However Semmelweis’ observations conflicted with the established scientific and medical opinions of the time and his ideas were rejected by the medical community; also because he could not offer an acceptable scientific explanation for his findings and practice! Semmelweis’ simple practice earned widespread acceptance only years after his death (Best and Neuhauser, 2004) .

However the tide was turning….with the help of “outsiders” ! The English physician, John Snow (1813-1858), who had his practice in Soho, London, was one of the first to use ether (diethylether), amylene (2-methyl -2 butene) and chloroform in the late 1840’s as anesthetics, allowing patients to undergo surgical and obstetric procedures without the usual pain and distress. Chloroform was easiest to apply, but it was seen at that time as unethical by most physicians and by the Church of England. However when on 7 April 1853 Queen Victoria asked John Snow to administer chloroform during the delivery of her eighth child Leopold, medical acceptance of his practice went growing and he became highly respected. John Snow was also skeptical about the then still dominant theory that diseases such as cholera and plague were caused by pollution or “bad air”. Based on his own direct observations – and that of local residents – of cholera patient cases ( his chemical and microscopic examination of water samples did not show or prove any danger ) and based on the spreading pattern of this outbreak in 1854 in his Soho neighborhood, he localized the source of the outbreak to be a public water pump situated in Broad Street, London. He convinced the local authorities to remove the handle to disable the pump, a simple action that ended the outbreak soon. Snow used maps to illustrate the cluster of cholera cases and statistics to proof a relation between water quality and “cholera poison“ cases (Hempel, 2006). He showed that the regional water supply companies were taking in water from sewage polluted sections of the Thames and delivered it (a. o. via public pumps) to the homes, resulting in the incidence of cholera outbreaks. These events led to the founding of the science of epidemiology, to a general improvement in public health and to fundamental changes in waste and water handling systems.

Famous French chemist and microbiologist Louis Pasteur (1822-1895) finally disproved the miasma theory and spontaneous generation and confirmed the germ theory of disease in 1861, too late for Semmelweis and Snow to build their important but contested findings and contributions on (Vandamme, 2019). It was the English surgeon Joseph Lister who introduced hygienic methods in surgery in the 1860’s with great success, admitting that he could build on Pasteur’s findings ! Lister was the son of Joseph Jackson Lister ((1786-1869), who improved the quality of microscopes by introducing achromatic object lenses. Lister initially studied botany at University College, London, but switched to medicine and graduated as Bachelor in Medicine, entering the Royal College of Surgeons at the age of 26. In 1854 he became first assistant of renown surgeon James Syme at the Royal Infirmary, University of Edinburgh, Scotland and was then appointed as Regius Professor of Surgery at the University of Glasgow, Scotland, where he became aware of Pasteur’s work on food spoilage by microbes; Pasteur had suggested three methods to eliminate these : filtration, heating and exposure to chemical “antiseptic”- solutions. Hospital wards at that time were only occasionally aired for short period as a precaution against the spread of infection via “miasma” or “ bad air “. Despite Semmelweis’ earlier advice, hospitals practiced surgery under really unsanitary conditions, with surgeons referring to the “good old surgical stink“ and taking pride in the blood and dirt stains on their operating gowns as a proof of their experience (Fitzharris, 2017). While in Glasgow, Lister decided to use Pasteur’s findings to treat wounds. Since filtration and heating were not suitable or too dangerous to treat human skin and tissue, he experimented in 1865 with a range of antiseptic products, that were then in use, such as wine, quinine, turpentine, diluted nitric acid, however with variable success; none were able to counteract pus formation and inflammations, mainly due to application after inflammation and putrefaction of tissue had already started. He looked for new compounds such as sodium permanganate and carbolic acid (phenol ), and tested them preventively and directly on the human skin or tissue. Lister had remembered that at a sewage treatment plant in Carlisle carbolic acid was in use to lower the stench of the air of rotting garbage and that of the fields, that were irrigated with sewage water. This suggestion was made to the sewage plant engineers by Professor Frederick Crace Calvert (1819-1873), chemist at the Royal Institute of Manchester. It was found that carbolic acid killed also the protozoal parasites of the cattle that grazed on the fields and pastures. Lister refined his carbolic acid applications, before and during operations, added it to wound dressings and bandages, used it to sterilize medical instruments and to wash hands, instructed to wear gloves, and he developed a spray apparatus to disinfect the air in the surgery room, … all with great success and seen as a real breakthrough! He published his results in 1867 in the authoritative The Lancet journal (Lister, 1867). He returned in 1869 to Edinburgh University as successor of Professor J. Syme and continued improving methods of antisepsis, yet he was still criticized by the medical profession! In 1876 he traveled to the USA on a lecturing trip, where his lectures and methods were initially seen as charlatanism, but he could convince Professor Henry J. Bigelow of Harvard University, Director of Massachusetts General Hospital in Boston, – and advocate to use ether as an anesthetic in surgery – of the merits of his antiseptic methods. Danish-born American physician Henry J. Garrigues (1831-1813) introduced antiseptic obstetrics in New York Maternity Hospital, USA, in the 1880’s based on Lister’s work.

In 1877 Lister returned to King’s College Hospital in London as professor in clinical surgery. Pasteur and Lister corresponded since 1871 but met first in person only in 1878. At Pasteur’s 70th birthday celebration in Paris in December 1892, Lister gave a praising speech about the life saving benefits of Pasteur’s research, … minimizing his own contributions! In 1883 he was elected President of the Clinical Society of London and from 1895 to 1900 he was president of the Royal Society. He received numerous honors and awards. The UK Discovery expedition of 1901-1904 named the highest peak in the Royal Society Range in Victoria Land, Antarctica, as Mount Lister. He died on 10 February 1912 at the age of 84 at his country home in Walmer, Kent, UK.

The slime mold Listerella first described in 1906, and the bacterial genus Listeria (described in 1927) with the well known foodborne pathogen Listeriamonocytogenes , causing listeriosis ( Radoshevich and Cossart, 2018 ), were named after him, and in daily life, his name is reflected in the popular ListerineR-mouthwash, available since 1879 in shops in the USA and eventually around the world!

6. From Listerine to other antiseptics and personal care products

The growing awareness of the existence and activities of microbes incited an obsession among the public for cleanliness and tidiness also in daily life (Ashenburg, 2009). A new generation of cleaning and personal hygiene products based on Lister’s carbolic acid emerged on the market. Chemist and medical doctor Joseph Joshua Lawrence had attended Lister’s lecture in 1876 at the International Medical Congress in Philadelphia, PA, USA, and being inspired by him, he concocted his own antiseptic brew in 1879 in St. Louis, IL,USA. His alcohol (27 %) based formula consisted of eucalyptol, menthol, methyl salicylate and thymol ( a commercial secret that he named “Listerine” in honor of Lister ), to be used as a general germicide and as surgical antiseptic. He licensed his formula to the local pharmacist Jordan Wheat Lambert in 1881. Lambert started the Lambert Pharmacal Company, marketing Listerine. Lambert sold it initially as an antiseptic, as a floor cleaner and even as a medicine to treat gonorrhea ! Only in the 1920’s became it really successful being advertised as a solution for “chronic“ halitosis (bad breath). In 1895 he advocated this product to dentists for oral care … and since then it became immortal. In 1955 the Lambert Co. merged with Warner-Hudnut Co. and became the Warner-Lambert Pharmaceutical Co., that was acquired by Pfizer Co. in 2000. Another attendant of the Philadelphia Congress of 1876 was Robert Wood Johnson; he started with his two brothers mass production of sterile bandages and sutures. The resulting company was called Johnson & Johnson … and the rest is history !

Nowadays a range of antiseptics are commonly used in medical settings as well as in personal care, cosmetic, sanitary and household products: alcohols ( ethanol, isopropanol, …), chlorohexidine-gluconate, octenidine dihydrochloride, hydrogen peroxide solutions, iodine-based solutions, polyhexanide (polyhexamethylene biguanide, PHMB), sodium hypochlorate solutions , … and several more. Whether microbes develop resistance towards long term use of antiseptics is not sufficiently documented; all seems to depend on the concentration range of application and on the frequency of use. Furthermore several antiseptic formulations are also in use as disinfectants. Whether cross-resistance to other antimicrobials, sanitizers and biocides occurs – as is the case with the now gradually banned disinfectant Triclosan – is not really known and deserves further investigation. Because of the now universal use of these antimicrobial chemicals, their environmental impact deserves more attention as well (Dhillon et al., 2015; Westgate et al., 2016).

Rosen, G. 1958. History of Public Health, pp. 369. John Hopkins University Press, USA.

Santer, M. 2009. Richard Bradley: a unified, living agent theory of the cause of infectious diseases of plants, animals, and humans in the first decades of the 18th century. Persp. Biol. Med. , 52(4), 566-578.